Rationalizing the Unprecedented Stereochemistry of an Enzymatic Nitrile Synthesis through a Combined Computational and Experimental Approach.

Abstract

In this contribution, the unique and unprecedented stereochemical phenomenon of an aldoxime dehydratase-catalyzed enantioselective dehydration of racemic E- and Z-aldoximes with selective formation of both enantiomeric forms of a chiral nitrile is rationalized by means of molecular modelling, comprising in silico mutations and docking studies. This theoretical investigation gave detailed insight into why with the same enzyme the use of racemic E- and Z-aldoximes leads to opposite forms of the chiral nitrile. The calculated mutants with a larger or smaller cavity in the active site were then prepared and used in biotransformations, showing the theoretically predicted decrease and increase of the enantioselectivities in these nitrile syntheses. This validated model also enabled the rational design of mutants with a smaller cavity, which gave superior enantioselectivities compared to the known wild-type enzyme, with excellent E-values of up to E>200 when the mutant OxdRE-Leu145Phe was utilized.

• Authors: Hilmi Yavuzer, Yasuhisa Asano, Harald Gröger
• Journal: Angewandte Chemie (International ed. in English) (Angew Chem Int Ed Engl) Vol. 60 Issue 35 Pg. 19162-19168 (08 23 2021) ISSN: 1521-3773 [Electronic] Germany
• PMID: 33886145 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

Chemical References

• Nitriles
• Hydro-Lyases
• aldoxime dehydratase

Topics

• Hydro-Lyases (chemistry, metabolism)
• Molecular Docking Simulation
• Molecular Structure
• Nitriles (chemistry, metabolism)
• Stereoisomerism